Sex differences have been observed in the clinical presentation of and vulnerability to various neuropsychiatric illnesses involving the striatum, including Parkinson's disease (Scott et al., 2000) and schizophrenia (Aleman et al., 2003). The striatum also is important in the rewarding effects of alcohol and other drugs of abuse. Interestingly, there is a higher prevalence of alcohol use disorders in males than females (National Household Survey, 2004). In attempts to elucidate the neurobiology underlying disorders that involve the striatum, researchers have thus focused on sex differences in the striatal dopaminergic system. We have recently demonstrated robust sex differences in ventral striatum dopamine release (DAR) following amphetamine administration in healthy, age-matched men and women. This is the first demonstration of gender-based DAR differences in human subjects. In this competitive renewal proposal, we are requesting funds to extend these important findings. Using PET imaging, we have established our ability to measure ethanol-induced DAR as oppose to the standard method of employing a stimulant drug to provoke DAR. Measurement of ethanol-induced DAR has greater utility for the field of alcohol research since it employs the actual substance administered by individuals with alcohol use disorders and does not rely on extrapolation from the techniques that administer amphetamine, methylphenidate or cocaine. Using PET imaging, we propose to compare the magnitude of ethanol-induced mesolimbic dopamine release in men and women. We will also examine the relationship between alcohol sensitivity (subjective and physiologic measures) and mesolimbic dopamine release. Finally, we will examine possible mechanisms for gender-based differences in dopamine release by studying the relationship between baseline and ethanol-stimulated sex hormones and neurosteroids with mesolimbic dopamine release. If our hypotheses of the roles of sex hormones/neurosteroid in DAR are supported, these findings will be important in understanding the etiology, epidemiology and treatment of alcohol abuse disorders. The scientific and clinical importance of the results also extends beyond addiction to include other disorders involving the striatum, such as schizophrenia, Parkinson's disease, Huntington's disease (Tamir et al., 1969), and obsessive-compulsive disorder (Bogetto et al., 1999).